Ferrostatin-1 protects against early sepsis-induced acute lung injury by suppressing lipid peroxidation–driven NINJ1-mediated DAMP release and neutrophil activation

Sepsis-induced acute lung injury (ALI) is a critical condition driven by neutrophil-dominated inflammation, lytic cell death and the subsequent DAMP release, etc. We tested whether the radical-trapping antioxidant Ferrostatin-1 (Fer-1) interrupts lipid peroxidation induced DAMP release and limits early lung injury in sepsis. We found that Fer-1 improved survival, preserved alveolar architecture, reduced lung-injury scores, and suppressed pulmonary inflammatory cytokine expression in a murine cecal ligation and puncture (CLP) model. Lung tissue RNA-sequencing showed that Fer-1 attenuated the CLP-induced inflammatory and chemotaxis transcriptome and significantly reduced neutrophil infiltration. In vitro , Fer-1 protected cells from lipid peroxidation–induced lytic death and impaired the release of large DAMPs associated with NINJ1 pathway, indicated Fer-1 acts upstream of NINJ1 to preserve membrane integrity. Fer-1 also directly lowered lipid peroxidation and reduced lipopolysaccharide (LPS)–induced IL-1β and IL-6 transcription and secretion in neutrophils, an effect reversed by pharmacological JNK/p38 activation. Together, our results indicate that Fer-1 functions as a dual-action modulator that prevents DAMP release and blunts neutrophil-driven inflammation escalation, thereby interrupting the lipid peroxidation–NINJ1–DAMP release axis, and mitigating early septic ALI. • Ferrostatin-1 (Fer-1) blunts early neutrophil infiltration and attenuates lung injury in the sepsis-induced acute lung injury. • Fer-1 reduces NINJ1-mediated DAMP release by maintaining plasma membrane integrity. • Fer-1 directly suppresses IL-1β/IL-6 production in primary neutrophils via inhibition of lipid peroxidation-induced JNK/p38 pathways.